Steroid, thyroid and retinoid hormones produce a diverse array of physiologic effects through the regulation of gene expression. Upon entering the cell, these hormones bind to a unique group of intracellular nuclear receptors which have been characterized as ligand-dependent transcription factors. This complex then moves into the nucleus where the receptor and its cognate ligand interact with the transcription preinitiation complex affecting its stability and ultimately the rate of transcription of the target genes.
The interactions of the liganded receptor with the specific elements in the promoter region of the target genes are mediated by multi-protein complexes. These complexes are composed of either corepressors, which inhibit transactivation or coactivators, which enhance transactivation (Glass et al., Curr. Opin. Cell. Biol., 1997, 9, 222-232). Several nuclear receptor coactivator proteins have been identified, all having similar biochemical properties. Recently, however, a novel coactivator was reported to be the first endogenous RNA transcript to function as an eukaryotic transcriptional coactivator. This coactivator, SRA, or steroid receptor RNA activator, has several unique features. SRA selectively interacts with the AF-1 domain of steroid hormone receptors found in the amino terminus of the receptor. Nuclear receptors contain two AF (activation function) domains responsible for their transcription activation function, and previously identified coactivators have all been shown to interact through the AF-2 domain.
SRA is also expressed as multiple isoforms in a tissue and cell-specific manner. Multiple transcripts of SRA were isolated and fell into two categories; a major transcript fraction of 0.7-0.85 kilobases (kb) in length producing a doublet and a minor transcript fraction of 1.3-1.5 kilobases. Of the two major transcripts in the doublet, the 0.7 kb species was expressed at significantly higher levels in breast cancer cell lines. All of the transcripts were found to exist at different levels in the tissues examined but were enriched in the liver and skeletal muscle.
Finally, SRA was found to be present in a preformed coregulator complex with the AF-2 coactivator, SRC-1. SRC-1 or steroid receptor coactivator-1 has been shown to enhance the transcriptional activity of the estrogen, glucocorticoid, thyroid, progesterone and retinoic acid receptors (Onate et al., Science, 1995, 270, 1354-1357). In immunoprecipitation experiments, it was shown that SRA acts as a component of distinct ribonucleoprotein complexes, one of which contains the nuclear receptor coactivator, SRC-1. Thus the SRA mRNA transcript itself, specifically expressed in steroid target tissues, functions as a component of a large multiprotein complex to selectively enhance transcriptional activation by steroid receptors.
Currently, there are no known therapeutic agents that effectively inhibit the synthesis of SRA. Consequently, there remains a long felt need for agents capable of selectively and effectively inhibiting SRA function.
Antisense technology is emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of SRA expression.